Efficient Bayesian-based Multi-View Deconvolution

Light sheet fluorescence microscopy is able to image large specimen with high resolution by imaging the sam- ples from multiple angles. Multi-view deconvolution can significantly improve the resolution and contrast of the images, but its application has been limited due to the large size of the datasets. Here we present a Bayesian- based derivation of multi-view deconvolution that drastically improves the convergence time and provide a fast implementation utilizing graphics hardware.Comment: 48 pages, 20 figures, 1 table, under review at Nature Method

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents

Predators reduce extinction risk in noisy metapopulations

Background Spatial structure across fragmented landscapes can enhance regional population persistence by promoting local “rescue effects.” In small, vulnerable populations, where chance or random events between individuals may have disproportionately large effects on species interactions, such local processes are particularly important. However, existing theory often only describes the dynamics of metapopulations at regional scales, neglecting the role of multispecies population dynamics within habitat patches. Findings By coupling analysis across spatial scales we quantified the interaction between local scale population regulation, regional dispersal and noise processes in the dynamics of experimental host-parasitoid metapopulations. We find that increasing community complexity increases negative correlation between local population dynamics. A potential mechanism underpinning this finding was explored using a simple population dynamic model. Conclusions Our results suggest a paradox: parasitism, whilst clearly damaging to hosts at the individual level, reduces extinction risk at the population level

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEAD227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a Kd of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEAD227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEAD227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10−10M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEAD227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEAD227A. Thus, 5T4FabV13-SEAD227A has highly attractive properties for therapy of human NSCLC. © 2001 Cancer Research Campaign http://www.bjcancer.co

Fear and Courage in Children: Two Sides of the Same Coin?

This study further investigated the construct of courage in children. Children aged 8–13 years (n = 51) were interviewed about the most courageous action that they had ever performed during their life, and to retrospectively rate their level of fear and courage experienced during that event. On a separate occasion, children also completed the Courage Measure for Children (CM-C) as an index of children’s general level of personal courage, as well as scales for assessing anxiety symptoms and sensation seeking. Results indicated that almost all children (i.e., 94%) indicated that they had carried out a courageous action at some point during their life, although the levels of fear and courage associated with these acts varied considerably. Further, there was no relation between fear and courage reported for the courageous action, but these variables were significantly correlated with respectively anxiety symptoms and personal courage as indexed by the CM-C. Finally, a significant positive correlation was observed between sensation seeking and personal courage, indicating that children who are more thrill and adventure seeking are generally also more courageous. It is concluded that fear and courage in children are largely unrelated and not just two sides of the same coin. The implications of these results for the etiology and treatment of childhood anxiety problems are discussed

Bayesian paternity analysis and mating patterns in a parasitic nematode, Trichostrongylus tenuis

Mating behaviour is a fundamental aspect of the evolutionary ecology of sexually reproducing species, but one that has been under-researched in parasitic nematodes. We analysed mating behaviour in the parasitic nematode Trichostrongylus tenuis by performing a paternity analysis in a population from a single red grouse host. Paternity of the 150 larval offspring of 25 mothers (sampled from one of the two host caeca) was assigned among 294 candidate fathers (sampled from both caeca). Each candidate father's probability of paternity of each offspring was estimated from 10-locus microsatellite genotypes. Seventy-six (51%) offspring were assigned a father with a probability of >0.8, and the estimated number of unsampled males was 136 (95% credible interval (CI) 77-219). The probability of a male from one caecum fathering an offspring in the other caecum was estimated as 0.024 (95% CI 0.003-0.077), indicating that the junction of the caeca is a strong barrier to dispersal. Levels of promiscuity (defined as the probability of two of an adult's offspring sharing only one parent) were high for both sexes. Variance in male reproductive success was moderately high, possibly because of a combination of random mating and high variance in post-copulatory reproductive success. These results provide the first data on individual mating behaviour among parasitic nematodes

Validity and reliability of Turkish version of "Hospital Survey on Patient Safety Culture" and perception of patient safety in public hospitals in Turkey

<p>Abstract</p> <p>Background</p> <p>The Hospital Survey on Patient Safety Culture (HSOPS) is used to assess safety culture in many countries. Accordingly, the questionnaire has been translated into Turkish for the study of patient safety culture in Turkish hospitals. The aim of this study is threefold: to determine the validity and reliability of the translated form of HSOPS, to evaluate physicians' and nurses' perceptions of patient safety in Turkish public hospitals, and to compare finding with U.S. hospital settings.</p> <p>Methods</p> <p>Physicians and nurses working in all public hospitals in Konya, a large city in Turkey, were asked to complete a self-administrated patient safety culture survey (n = 309). Data collection was carried out using the Turkish version of HSOPS, developed by Agency for Healthcare Research and Quality (AHRQ). Data were summarized as percentages, means, and SD values. Factor analysis, correlation coefficient, Cronbach's alpha, ANOVA, and t tests were employed in statistical analyses. Items on patient safety were categorized into 10 factors. Factor loadings and internal consistencies of dimension items were high.</p> <p>Results</p> <p>Most of the scores related to dimensions, and the overall patient safety score (44%) were lower than the benchmark score. "Teamwork within hospital units" received the highest score (70%), and the lowest score belonged to the "frequency of events reported" (15%). The study revealed that more than three quarters of the physicians and nurses were not reporting errors.</p> <p>Conclusion</p> <p>The Turkish version of HSOPS was found to be valid and reliable in determining patient safety culture. This tool will be helpful in tracking improvements and in heightening awareness on patient safety culture in Turkey.</p

Development of a novel small antibody that retains specificity for tumor targeting

<p>Abstract</p> <p>Background</p> <p>For the targeted therapy of solid tumor mediated by monoclonal antibody (mAb), there have different models of rebuilding small antibodies originated from native ones. Almost all natural antibody molecules have the similar structure and conformation, but those rebuilt small antibodies cannot completely keep the original traits of parental antibodies, especially the reduced specificity, which gravely influences the efficacy of small antibodies.</p> <p>Methods</p> <p>In this study, authors developed a novel mimetic in the form of V_HFR1_C-10-V_HCDR1-V_HFR2-V_LCDR3-V_LFR4_N-10for a parental mAb induced with human breast cancer, and the mimetic moiety was conjugated to the C-terminal of toxicin colicin Ia. The novel fusion peptide, named protomimecin (PMN), was administered to MCF-7 breast cancer cells to demonstrate its killing competency <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>Compared with original antibody-colicin Ia (Fab-Ia) and single-chain antibody-colicin Ia (Sc-Ia) fusion proteins, PMN retained the targeting specificity of parental antibody and could specifically kill MCF-7 cells <it>in vitro</it>. By injecting intraperitoneally into BALB/c athymic mice bearing MCF-7 tumors, with reduced affinity, PMN significantly suppressed the growth of tumors compared with control mice treated by toxicin protein, Fab-Ia protein, Sc-Ia protein or by PBS (<it>p </it>< 0.05).</p> <p>Conclusion</p> <p>This novel mimetic antibody retained original specificity of parental antibody, and could effectively guide killer moiety to suppress the growth of breast cancer by targeted cell death.</p

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr